title: Regenerative hyperplasia is not required for liver tumor induction in female B6C3F1 mice exposed to trihalomethanes.
abstract: Chloroform (TCM), a water disinfection by-product, induced liver tumors in female mice when administered by gavage in corn oil but not when given in drinking water at comparable daily doses. Because short-term studies showed that the gavage doses also induced liver toxicity, it has been suggested that the liver tumor response occurs secondary to cytotoxicity and consequent regenerative hyperplasia induced by oxidative metabolism of TCM to the toxic dihalocarbonyl intermediate. This study compares dose-response relationships of gavage-administered chlorinated/brominated trihalomethanes for hepatotoxicity, replicative DNA synthesis, and hepatocarcinogenicity in female B6C3F1 mice. The liver tumor data were obtained from previously published studies. Because bromine is a better leaving group than chlorine, metabolism of bromodichloromethane (BDCM) should produce the same intermediates as would be formed from TCM. Hence, the toxicity and carcinogenicity of BDCM was expected to be qualitatively similar to that of TCM. Dose responses for liver weight, serum sorbitol dehydrogenase and alanine aminotransferase (ALT) activities, hepatocyte degeneration, and hepatocyte labeling index (LI, a measure of replicative DNA synthesis) in female mice were similar following 3 weeks of gavage administration (once per day, 5 days per week) with TCM, BDCM, or chlorodibromomethane (CDBM). Fits of composite data for these trihalomethanes to a Hill equation model revealed sigmoidal dose responses for ALT activity and hepatocyte LI and a nearly linear low-dose response for liver tumor incidence. For this family of chemicals, the mouse liver tumor response was not associated with an elevated hepatocyte LI at doses of approximately 1 mmol/kg or less. High incidences of liver tumors were observed with BDCM and CDBM at doses that had a marginal effect or no effect on the hepatocyte LI. Thus, the carcinogenic effects of trihalomethanes are not simply a consequence of cytotoxicity and regenerative hyperplasia. The possible contributions from other activation pathways, including GSH conjugation and reductive metabolism, need to be considered in assessments of the carcinogenicity of the trihalomethanes.
authors.affiliation: Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. melnickr@niehs.nih.gov
authors.forename: R L
authors.initials: RL
authors.lastname: Melnick
authors.forename: M C
authors.initials: MC
authors.lastname: Kohn
authors.forename: J K
authors.initials: JK
authors.lastname: Dunnick
authors.forename: J R
authors.initials: JR
authors.lastname: Leininger
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002725:Chloroform / Q000633:toxicity; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006842:Hydrocarbons, Brominated / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D006965:Hyperplasia / Q000139:chemically induced; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D022882:Trihalomethanes
chemical_list: D002273:Carcinogens; D006842:Hydrocarbons, Brominated; D006846:Hydrocarbons, Halogenated; D022882:Trihalomethanes; C032707:chlorodibromomethane; C025191:bromodichloromethane; D002725:Chloroform; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; C015044:bromoform